Abrogation of human chronic myeloid leukemia cells insensitivity to adriamycin and mitoxanthrone cytotoxicity by quinidine.
The inherent, insensitive nature of human chronic myeloid leukemia (CML) cells to antiproliferative effects of adriamycin (ADR) disallows its utility in the clinics. Efforts were directed towards sensitizing CML cells to ADR and mitoxanthrone (MITO) cytotoxicity by employing quinidine, an antiarhythmic agent. Inhibition of radiolabeled thymidine incorporation into DNA was used as a measure of drug activity. A dose-dependent inhibition of DNA biosynthesis was observed with increasing concentrations of ADR (0.1 to 100 micrograms/ml), MITO (0.05 to 5 micrograms/ml) and quinidine (0.1 to 50 mumol/l). When the CML cells were exposed to quinidine and ADR/MITO simultaneously, the observed enhancement in the antiproliferative activity of the anticancer drug was markedly less as compared to the inhibition of DNA synthesis observed in CML cells pretreated with quinidine for 1 h prior to exposure to the cytotoxic drugs. Pretreatment of CML cells with quinidine resulted in a significantly (p less than 0.001) increased synergistic inhibition of DNA biosynthesis which was completely irreversible. Results highlight the utility of quinidine as a drug response modulator in a schedule-dependent manner to potentiate the cytotoxicity of ADR and MITO and warrants further studies into a possible role of quinidine to increase the chemotherapeutic efficacy of antineoplastic drugs in the clinics.
Parekh
H K
HK
Cellular Chemotherapy Unit, Tata Memorial Center, Parel, Bombay, India.
Advani
S H
SH
Chitnis
M P
MP
D002470:Cell Survival / Q000187:drug effects*; D004261:DNA Replication / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004317:Doxorubicin / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000473:pathology*; D008942:Mitoxantrone / Q000494:pharmacology*; D011802:Quinidine / Q000494:pharmacology*; D013936:Thymidine / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects
D004273:DNA, Neoplasm; D004317:Doxorubicin; D008942:Mitoxantrone; D011802:Quinidine; D013936:Thymidine